Primary wild type and COX-2-/- keraticytes were transfected with a retrovirus containing v-H-ras and the transfected keratinocytes grafted on to the backs of athymic nude mice. Tumor incidence and tumor size resulting from transfected COX-2 -/- keratinocytes was markedly reduced compared to tumors produced by transfected wild type keratinocytes. Lower proliferation rates and higher levels of terminal differentiation were observed in papillomas derived from the COX-2 -/- keratinocytes compared to papillomas derived from wild type keratinocytes. The levels of Ras expression were similar in both wild type and COX-2-/- tumor cells, however, the levels of p-EGFR and p-ERK1/2 were lower in papillomas derived from COX-2-/- keratinocytes compared to papillomas derived from wild type keratinocytes indicating that COX-2 deficiency decreased growth promoting signaling pathways down stream of v-H-Ras. The extents of vascularization and the levels of apoptosis were similar in wild type and COX-2-/- tumors, indicating that neither was not a factor in reducing COX-2-/- tumor size. . Thus, the deficiency of COX-2 in the transformed keratinocyte itself was sufficient to decrease tumor growth independent of systemic COX-2 expression.